SAR407899 HCl is a novel, potent, selective, and ATP-competitive ROCK inhibitor with an IC50 of 135 nM for ROCK-2, and Kis of 36 nM and 41 nM for human and rat ROCK-2, respectively. In a panel of 117 receptor and enzyme targets, SAR407899 exhibits a high degree of selectivity. About eight times as active as fasudil is SAR407899. Concentration-dependent inhibition of thrombin-induced stress fiber formation, platelet-derived growth factor-induced proliferation, and monocyte chemotactic protein-1-stimulated chemotaxis were all shown in vitro by SAR407899. Different species and vascular beds' isolated precontracted arteries were potently (mean IC(50) values: 122 to 280 nM) and species-independently relaxed by SAR407899. In vivo, SAR407899 lowered blood pressure in a range of rodent models of arterial hypertension, over a dose range of 3-25 mg/kg PO. Y-27632 and facudil did not have the same antihypertensive effect as SAR407899. In conclusion, SAR407899 shows promise as an antihypertensive agent and is a new and powerful selective Rho-kinase inhibitor.
Physicochemical Properties
| Molecular Formula | C14H17CLN2O2 |
| Molecular Weight | 280.7500 |
| Exact Mass | 280.098 |
| Elemental Analysis | C, 59.89; H, 6.10; Cl, 12.63; N, 9.98; O, 11.40 |
| CAS # | 923262-96-8 |
| Related CAS # | SAR407899;923359-38-0 |
| PubChem CID | 42635918 |
| Appearance | Light yellow to khaki solid |
| LogP | 2.789 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 2 |
| Heavy Atom Count | 19 |
| Complexity | 337 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | Cl.O=C1C2C(=CC(=CC=2)OC2CCNCC2)C=CN1 |
| InChi Key | KMNVOGVCCZNVNU-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C14H16N2O2.ClH/c17-14-13-2-1-12(9-10(13)3-8-16-14)18-11-4-6-15-7-5-11;/h1-3,8-9,11,15H,4-7H2,(H,16,17);1H |
| Chemical Name | 6-piperidin-4-yloxy-2H-isoquinolin-1-one;hydrochloride |
| Synonyms | 6-(piperidin-4-yloxy)isoquinolin-1(2H)-one hydrochloride; SAR-407899 hydrochloride; SAR407899 (hydrochloride); SAR407899 hydrochloride; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | ROCK-2 (IC50 = 102 nM); ROCK-1 (IC50 = 276 nM) |
| ln Vitro | SAR407899 hydrochloride is a potent and ATP-competitive ROCK inhibitor, with Kis of 36 nM and 41 nM for human and rat ROCK-2, respectively. SAR407899 inhibits ROCK-2 more effectively than ROCK-1, with IC50 values of 102±19 nM and 276±26 nM, respectively, when 40 μM ATP is present. SAR407899 has IC50s of 5.4 and 3.1 μM, respectively, which indicates that it inhibits PKC-Δ and MSK-1 less potently. The ROCK-mediated phosphorylation of MYPTT696 in HeLa cells stimulated with PHEN is specifically inhibited by SAR407899 (0.1, 0.3, 1.0, and 3.0 μM). This effect is also observed at 1 μM and 10 μM in primary rat aortic smooth muscle cells. SAR407899 (3 μM) totally prevents the development of stress fibers and the thrombin-induced shrinkage of human umbilical vein endothelial cells (HUVECs). With an IC50 of 5.0±1.3 μM, SAR407899 concentration-dependently inhibits 5-bromodeoxyuridine incorporation into the cells. THP-1 migration is also effectively inhibited by SAR407899, with an IC50 of 2.5±1.0 μM. With IC50 values ranging from 122 to 280 nM, SAR407899 exhibits strong vasorelaxant activity in a wide range of isolated arteries taken from various vascular beds and species[1]. SAR407899, with IC50s of 0.07 and 0.05 μM, respectively, relaxes the phenylephrine pre-contracted smooth muscle in a dose-dependent manner[2]. |
| ln Vivo | SAR407899 (3 mg/kg, i.v.) suppresses the phosphorylation of MYPTT696 by ROCK in the thoracic aorta of rats that develop spontaneous hypertension (SHRs). In rats, SAR407899 (0.01-0.30 mg/kg, i.v.) effectively decreases pressor responses to vasoconstrictor agents. Hypertensive SHRs' blood pressure is dose-dependently lowered by SAR407899 (1, 3, 10, and 30 mg/kg, p.o.)[1]. In rabbits in good health, SAR407899 (1-3 mg/kg, i.v. or 3, 10 mg/kg, p.o.) lengthens the penis. In diabetic rabbits, SAR407899 (3-10 mg/kg, p.o.) likewise lengthens the penile in a dose-dependent manner[2]. |
| Animal Protocol | SAR407899 is administered intravenously (i.e., in an ear vein) in increasing doses to rabbits, orally (1, 3, 10, 30 mg/kg) or in combination with sildenafil (2 or 6 mg/kg). Every animal is used multiple times with a week's washout in between for various doses and agents. Using a sliding digital caliper, the length (mm) of the exposed penile mucosa (penile erection parameter) is measured at various time intervals. The findings are presented as the penile length of three to five rabbits, mean ± SEM[2]. |
| References |
[1]. Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor. Hypertension. 2009 Sep;54(3):676-83. [2]. Erectile properties of the Rho-kinase inhibitor SAR407899 in diabetic animals and human isolated corpora cavernosa. J Transl Med. 2012 Mar 23;10:59. [3]. Screening RhoA/ROCK inhibitors for the ability to prevent chronic rejection of mouse cardiac allografts.Transpl Immunol. 2018 Jun 6. pii: S0966-3274(18)30029-7. |
Solubility Data
| Solubility (In Vitro) |
Water: ~56 mg/mL (~199.5 mM) Ethanol: ~1 mg/mL (~3.6 mM) DMSO: ~28 mg/mL (~99.7 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (8.90 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (8.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 25 mg/mL (89.05 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.5619 mL | 17.8094 mL | 35.6189 mL | |
| 5 mM | 0.7124 mL | 3.5619 mL | 7.1238 mL | |
| 10 mM | 0.3562 mL | 1.7809 mL | 3.5619 mL |